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Compositions and methods for regulating cell-cell fusion through medium conductance calcium-activated potassium channels

一种细胞融合、钙激活的技术，应用在受体/细胞表面抗原/细胞表面决定因子、融合细胞、药物组合等方向

Inactive Publication Date: 2011-12-07
BOEHRINGER INGELHEIM INT GMBH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Unfortunately, the mechanism by which macrophages fuse with themselves and other cells remains largely unknown

Method used

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  • Compositions and methods for regulating cell-cell fusion through medium conductance calcium-activated potassium channels
  • Compositions and methods for regulating cell-cell fusion through medium conductance calcium-activated potassium channels
  • Compositions and methods for regulating cell-cell fusion through medium conductance calcium-activated potassium channels

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0304] Genome-wide cDNA microarrays were used to identify genes belonging to the fusion machinery, and KCNN4 / SK4 was identified to be highly expressed in osteoclasts and giant cells, but only at the onset of macrophage fusion.

[0305] Materials and methods

[0306] animals and cells. sk4 was obtained on the basis of mixed 129J / C57BL6 as previously described - / - Mice were bred and genotyped (Begenisich et al. (2004) J. Biol. Chem. 279(46):47681-47687). Animals were housed in standard cages with a 12 hour photoperiod and provided ad libitum access to rodent chow (Harlan Teklad #2018) and water. Mice were sacrificed at 8 weeks of age. Mice received two intraperitoneal (i.p.) injections of calcein (5 mg / kg / day) on day 8 and one prior to sacrifice for dynamic histomorphometric analysis.

[0307] reagent. MSC-F and RANKL were purchased from PreproTech (Rocky Hill, NJ). Phalloidin-Alexa fluor 568 was purchased from Invitrogen (Carlsbad, CA), and osteologic slides were purchase...

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Abstract

Compositions and methods are provided for modulating cell-cell fusion by using agents that modulate expression, activity, or function of intermediate- conductance calcium-activated potassium (SK4) channel. In some embodiments, the compositions and methods of the invention provide for inhibition of multi-nucleated osteoclastogenesis and cell-cell fusion, especially cell fusion involving macrophages. In such embodiments, the compositions can comprise inhibitory nucleic acids, monoclonal antibodies or small molecule inhibitors of the SK4 channels and find use in preventing and / or treating various diseases or disorders including bone loss, autoimmune and inflammatory diseases or disorders, implant and transplant rejection, and cancer metastasis. In other embodiments, the compositions and methods of the invention provide for activation of cell-cell fusion. Also provided are methods to screen for SK4 channel modulators (inhibitors or activators) that modulate cell-cell fusion, particularly macrophage cell fusion.

Description

technical field [0001] The present invention relates generally to compositions and methods for modulating cell-cell fusion (also known as cellocytosis), and more particularly to compositions and methods for modulating homotypic and heterotypic cell-cell fusion of macrophages. The present invention thus provides compositions and methods for modulating cell fusion, and osteoclast differentiation and function associated with various diseases or disorders. Background technique [0002] Cell fusion is an important biological event, necessary for a variety of developmental and homeostatic processes. Although intracellular membrane fusion is well known during organelle trafficking, less is known about mediating sperm-oocyte, myoblast-myoblast, cell-cell fusion, and macrophage-macrophage fusion few. See Vignery (2000) Int. J. Exp. Pathol. 81:291-304. [0003] In the case of macrophages, these cells can fuse with themselves in tissues (ie, homotype fusion) to form giant cells, whi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/705
CPCC07K14/705A61P19/00A61P19/08A61P29/00A61P35/00A61P35/04A61P37/00A61P37/06A61P43/00A61K39/395A61K38/17C12N5/12C07K16/18
Inventor 李军阿格尼斯.维格纳里
Owner BOEHRINGER INGELHEIM INT GMBH
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